Synthesis of manzacidin A and C: Efficient construction of quaternary carbon stereocenters bearing nitrogen substituents

Article abstract of DOI:10.1039/c1ob06559a

An efficient synthetic method for stereoselective construction of asymmetric quaternary carbon stereocenters, bearing nitrogen in the form of Boc-protected allyl amines, has been developed. This methodology is employed in the synthesis of marine alkaloids

Full text of DOI:10.1039/c1ob06559a

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PAPER
Synthesis of manzacidin A and C: efficient construction of quaternary carbon
stereocenters bearing nitrogen substituents†
Yoshiyasu Ichikawa,*a Ken Okumura,a Yasunori Matsuda,a Tomoyuki Hasegawa,a Mitsuhiro Nakamura,b
Aya Fujimoto,b Toshiya Masuda,b Keiji Nakanoa and Hiyoshizo Kotsukia
Received 12th September 2011, Accepted 5th October 2011
DOI: 10.1039/c1ob06559a
An efficient synthetic method for stereoselective construction of asymmetric quaternary carbon
stereocenters, bearing nitrogen in the form of Boc-protected allyl amines, has been developed. This
methodology is employed in the synthesis of marine alkaloids, manzacidin A and C.
Their unique structures coupled with their scarcity from the
natural sources make manzacidin A and C attractive targets
Stereoselective synthesis of quaternary stereocenters is one of the
for total synthesis. The most critical problem confronted in the
Introduction
most challenging problems in modern organic chemisry.1 Among
synthesis of these targets is the construction of a quaternary
quaternary stereocenters, nitrogen-substituted quaternary chiral
stereogenic carbon center bearing nitrogen. Previous syntheses
centres have attracted our continuous interest, because they serve
present elegant approaches to this problem and, as a result,
as important architectural elements in a variety of nitrogen-
syntheses of manzacidins have showcased the power of novel
containing natural products.2 In order to address the problems
associated with installation of quaternary stereocenters bearing
nitrogen, we have focused on the allyl cyanate-to-isocyanate
rearrangement, which is a highly stereoselective carbon–nitrogen
bond forming process at sterically encumbered positions.3 Recent
investigations aimed at developing the preparative utility of this
process led us to explore stereoselective routes for the synthesis of
marine alkaloids, manzacidin A and C.
In 1991, Kobayashi and his co-workers reported the isolation
of a novel class of bromopyrrole alkaloids, manzacidin A (1) and
C (2) (Fig. 1), from the marine sponge Hymeniacidon sp. collected
at the Manza beach of Okinawa island in Japan.4 Ohfune and
co-workers reported the first syntheses of manzacidin A and C
that served to confirm the relative and absolute stereochemistry of
these compounds.5
synthetic methodologies.6
Results and discussion
Retrosynthetic analysis of manzacidin A (1) is shown in Scheme
1. The structure of manzacidin A (1) can be simplified to tetrahy-
dropyrimidine 3 by removal of the 3-bromopyrrole-5-carboxylic
acid moiety. Consideration of preparing a,g-diamino-d-hydroxy
acid 3 by employing allyl cyanate-to-isocyanate rearrangement
led to the identification of Boc-carbamate 4 as a key intermediate.
We envisioned that dehydration of carbamate 7 could generate
the allyl cyanate 6, which could then undergo [3,3] sigmatropic
rearrangement attended by [1,3]-chiral transfer to produce 5
Fig. 1 Manzacidin A (1) and C (2).
aFaculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan.
E-mail: ichikawa@kochi-u.ac.jp
bFaculty of Integrated Arts and Sciences, University of Tokushima,
Tokushima 770-8502, Japan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06559a
Scheme 1 Retrosynthetic plan of manzacidin A (1).
614 | Org. Biomol. Chem., 2012, 10, 614–622
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that contains a quaternary carbon bearing nitrogen in the form
of an isocyanate.7 Isocyanate 5 could be transformed to the
Boc-carbamate 4 by reaction with tert-butyl alcohol. Further
retrosynthesis of g,d-unsaturated a-amino acid 7 sets up 8b as
a chiral starting material, which would derive from commercially
available (-)-methyl L-lactate 8a by silylation.
We believed that the development of this strategy would lead
to a significant expansion of the utility of the allyl cyanate-to-
isocyanate rearrangement to access valuable allyl amine deriva-
tives. However, two key questions needed to be addressed in
order to assess the feasibility of our approach to manzacidin
A (1). Firstly, the ally cyanate 6 would have to be generated
from 7 without disturbing the N,N-dicarbamoyl-protected amine,
methyl ester and the stereogenic center in the racemization prone
N-protected a-amino acid ester. Secondly, the Boc-carbamate 4
would need to be prepared by reaction of the sterically encumbered
isocyanate 5 with t-butyl alcohol without affecting the functional
groups within 5.
Our initial studies focused on the conversion of sterically
crowded isocyanates into the Boc-carbamates. For this purpose,
the model isocyanate 12 was prepared from geraniol (9) (Scheme
2) and its reaction with tert-butyl alcohol was examined. Dis-
appointingly, our previously reported protocols using stannous
alkoxide (Bu3SnOt-Bu)8 and catalyst (dibutyltin maleate)9 gave
the Boc-carbamate 13 in only low yields; however, screening
several alkoxides led to the finding that reaction of isocyanate
12 with lithium t-butoxide provided the Boc-carbamate 13 in 81%
yield (method A).10 Furthermore, it was found that addition of
tert-butyl alcohol to isocyanate 12 proceeded smoothly in the
presence of chlorotrimethylsilane (TMSCl) to furnish 13 in 85%
yield (method B).11 The two methods are complementary (basic
vs. acidic conditions) and have the merit of utilizing commonly
available reagents.12
Scheme 3 Synthesis of the g,d-unsaturated a-amino acid 17 by diastereo-
selective hydrogenation.
with DuPHOS-Rh catalyst reported by Burk and co-workers.13
Accordingly, dienamide 16 was prepared by a three-step sequence
involving DIBAL reduction, TEMPO oxidation and Horner–
Emmons olefination using Schmidt’s reagent14 to afford 16 in
61% yield over three steps. Initially, we had little confidence
that diastereoselective hydrogenation of 16 would be successful,
because Burk noted that N-Cbz protected a,g-dienamide esters
do not undergo asymmetric hydrogenation with DuPHOS-Rh
catalysts. Contrary to our apprehension, enamide 16 was found
to undergo hydrogenation in the presence of 5 mol% catalyst in
methanol under hydrogen (0.6 MPA) to furnish the desired g,d-
unsaturated amino acid 17 predominantly.15
In order to check the diastereoselectivity of the hydrogenation
of 16 and to prepare the intermediate for manzacidin C, ent-allyl
alcohol 15, prepared from (+)-methyl D-lactate,16 was elaborated
to 18 (Scheme 4) in a manner that is identical to that described
in Scheme 3. Importantly, no signals corresponding to 18 were
observed in the 1H NMR spectrum of 17.
Scheme 2 Transformation of a sterically crowded model isocyanate into
a Boc-carbamate.
Having established conditions for the conversion of sterically
crowded isocyanates into the Boc-carbamates, we initiated the syn-
thesis of manzacidin A starting with commercially available (-)-
methyl L-lactate 8a (Scheme 3). Protection of the hydroxyl group
in 8a as TBDPS ether, followed by diisobutylaluminium hydride
(DIBAL) reduction of 8b and Wittig olefination produced the
(E)-a,b-unsaturated ester 14 exclusively in 92% yield. Installation
of the g,d-unsaturated a-amino acid moiety was performed using
enantioselective catalytic hydrogenation of a,g-dienamide esters
Scheme 4 Synthesis of the diastereomer 18 from the ent-allyl alcohol 15.
With 17 in hand, we were positioned to examine installation
of the key quaternary asymmetric carbon center exploiting allyl
cyanate-to-isocyanate rearrangement (Scheme 5). Initial efforts
showed that a problem existed in that a urea was formed by
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Scheme 6 Synthesis of manzacidin A (1).
Scheme 5 Allyl cyanate-to-isocyanate rearrangement of 6 and conversion
to Boc-carbamate 4.
intramolecular capture of the formed isocyanate by the nitrogen
in the Cbz group (eqn (1)).
(1)
To prevent this process, the nitrogen in the Cbz group was
masked as the bis-carbamate protected amine 19 by treatment of
17 with Boc2O and DMAP.17 Deprotection of the TBDPS group
in 19 followed by carbamoylation of the resulting allyl alcohol
20 by treatment with trichloroacetyl isocyanate and methanolysis
of the resulting N-trichloroacetylcarbamate produced allyl car-
bamate 7. Dehydration of 7 utilizing triphenylphosphine, carbon
tetrabromide and triethylamine in CH2Cl2 at -10 ◦C generated the
allyl cyanate 6, which uneventfully underwent rearrangement to
form the allyl isocyanate 5. After careful isolation, isocyanate 5
was immediately transformed to the Boc-carbamate 4 in 78% yield
employing method B described in Scheme 2.
The remaining tasks were synthesis of the lactone interme-
diate 22 and its conversion to manzacidin A (1). To this end,
ozonolysis of 4 was carried out at -78 ◦C in a mixture of
CH2Cl2 and methanol. Without isolation, the resulting aldehyde
was reduced with sodium borohydride to afford 21 in 89% yield.
Hydrogenolysis to remove the Cbz group in 21 followed by heating
a solution of the resulting methyl ester in toluene provided the
crystalline lactone 22 in 76% yield over two steps. Following
the procedures reported by Ohfune and co-workers,5,6k sequential
deprotection of the Boc group in 22 with trifluoroacetic acid
(TFA) in CH2Cl2 and treatment of the hydrolysate with a mixture
of methyl orthoformate and TFA was carried out in one flask
to give rise to the tetrahydropyrimidine 3 after ion exchange
chromatography in 89% yield. Finally, coupling of 3 with 2-
(trichloroacetyl)-4-bromopyrrole with sodium hydride in DMF
and HPLC purification furnished manzacidin A (1) in 46% yield.
In addition, we carried out a synthesis of manzacidin C (2)
(Scheme 7). The procedures used for conversion of 17 to 4 (Scheme
5) and from 4 to 22 (Scheme 6) were repeated using 18 and 24,
respectively, to furnish the lactone 25 in 32% overall yield from 18
in 8 steps. Since lactone 25 was employed as an intermediate in the
Scheme 7 Formal synthesis of manzacidin C (2).
synthesis of manzacidin C by Ohfune,5 this sequence represents a
formal synthesis of manzacidin C.
Conclusions
In summary, we have developed a practical procedure for stereos-
elective construction of asymmetric quaternary carbon stereocen-
ters bearing nitrogen in the form of Boc-protected allyl amines.
In addition, this process served as a key step in the synthesis of
marine alkaloids, manzacidin A and C. Importantly, generation
of the allyl cyanate 6, its rearrangement and transformation of the
sterically encumbered cyanate 5 into the Boc-carbamate 4 were
carried out in the presence of labile functionality as well as an
a-stereogenic center present in the a-amino acid moiety.18
Experimental
General
Melting points were recorded on a micro melting point apparatus
and are not corrected. Optical rotations were measured at the
sodium D line with a 100 mm path length cell, and are reported
as follows: [a]TD, concentration (g/100 mL), and solvent. Infrared
1
spectra are reported in wave number (cm-1). H NMR data are
reported with the solvent resonance as the internal standard
relative to chloroform (d 7.27), methanol (d 3.31) and DOH (d
4.80) as follows; chemical shift (d), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, br = broadened, m = multiplet),
coupling constants (J, given in Hz) and integration. 13C NMR
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chemical shifts (d) are recorded in parts per million (ppm) relative
to CDCl3 (d 77.0), CD3OD (d 49.0) and t-BuOH (d 30.29 in D2O)
as internal standards. High-resolution mass spectra (HRMS)
are reported in m/z. Reactions were run under atmosphere of
argon when the reactions were sensitive to moisture or oxygen.
in CH2Cl2 (4.0 mL) dropwise. After being stirred at -10 ◦C for 30
min, the reaction mixture was diluted with hexane. The mixture
was washed with H2O (3 times) and brine, dried over Na2SO4 and
concentrated under reduced pressure to give crude allyl isocyanate
12, which was immediately used for the subsequent reaction.
Crude allyl isocyanate 12 was dissolved in CH2Cl2 (5.0 mL),
and then treated with trimethylchlorosilane (3 mL, 0.03 mmol)
and tert-butyl alcohol (0.48 mL, 5.1 mmol) at room temperature.
After being stirred at room temperature for 25 h, the solvent
was removed under reduced pressure and the crude product was
purified by silica gel chromatography (AcOEt–hexane 1 : 20) to
afford Boc-carbamate 13 (109 mg, 85% from geraniol 9) as a
colorless liquid; IR (NaCl) nmax 3450, 3361, 2975, 2929, 1725, 1698,
1492, 1249, 1169, 1069 cm-1; 1H NMR (CDCl3, 400 MHz) d 1.37
(s, 3H), 1.43 (s, 9H), 1.59 (s, 3H), 1.68 (s, 3H), 1.95 (brq, J = 7.5 Hz,
2H), 4.62 (br, 1H), 5.03–5.13 (3H), 5.89 (dd, J = 17.0, 11.0 Hz, 1H);
13C NMR (CDCl3, 100 MHz) d 17.5, 22.5, 24.8, 25.6, 28.4, 39.5,
56.1, 78.8, 78.8, 111.9, 124.0, 131.8, 143.6, 154.3; HRMS (ESI):
m/z calcd for C15H28NO2 (M+ H)+ 254.21200, found 254.2114.
˚
Dichloromethane was dried over 3 A molecular sieves. Pyridine
and triethylamine were stocked over anhydrous KOH. All other
commercially available reagents were used as received.
(E)-3,7-Dimethylocta-2,6-dienyl carbamate (10). To a solution
of geraniol (9) (1.78 g, 11.5 mmol) in CH2Cl2 (115 mL) cooled to
0 ◦C was added trichloroacetyl isocyanate (1.40 mL, 17.3 mmol).
◦
After stirring at 0 C for 30 min, the solution was concentrated
under reduced pressure. The resulting residue was dissolved in
a mixture of MeOH (70 mL) and 1 M aqueous potassium
carbonate (45 mL). After stirring at room temperature for 3 h,
the separated aqueous layer was extracted with CH2Cl2 (3 times).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and then concentrated under reduced pressure.
Purification by silica gel chromatography (AcOEt–hexane 1 : 4 to
1 : 2) afforded carbamate 10 (2.33 g, 102%), which was used for the
next reaction without further purification; IR (NaCl) nmax 3439,
3344, 2967, 2918, 2855, 1712, 1606, 1049 cm-1; 1H NMR (CDCl3,
400 MHz) d 1.62 (s, 3H), 1.69 (s, 3H), 1.71 (s, 3H), 2.00–2.15 (4H),
4.59 (d, J = 7.0 Hz, 2H), 4.92 (br, 2H), 5.09 (brt, J = 7.0 Hz, 1H),
5.35 (t, J = 7.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 16.4, 17.6,
25.6, 26.2, 39.5, 61.9, 118.4, 123.7, 131.8, 142.1, 157.2; HRMS
(ESI): m/z calcd for C11H19NO2Na (M+ Na)+ 220.13135, found
220.1315.
(S)-Methyl 2-(tert-butyldiphenylsilyloxy)propanoate (8b). To a
solution of L-(-)-lactic acid methyl ester (8a) (4.36 g, 41.9 mmol)
and imidazole (8.5 g, 0.12 mol) in DMF (23.0 mL) was added
tert-butylchlorodiphenylsilane (10.9 mL, 41.9 mmol) portionwise.
The reaction mixture was stirred at room temperature for 48 h,
and then diluted with Et2O (120 mL) and H2O (100 mL). The
separated organic layer was washed with H2O, brine, and dried
over Na2SO4. Concentration under reduced pressure provided the
crude silyl ether 8b (14.8 g), which was used for the next reaction
without further purification; [a]1D6 -44.7 (c 1.00, CHCl3); IR (NaCl)
1
nmax 2952, 2933, 1758, 1739, 1112 cm-1; H NMR (CDCl3, 400
tert-Butyl 3,7-dimethylocta-1,6-dien-3-ylcarbamate (13) pre-
pared using method A. To a solution of allyl carbamate 10
(200 mg, 1.01 mmol), triphenylphosphine (665 mg, 2.53 mmol)
and triethylamine (0.45 mL, 3.24 mmol) in CH2Cl2 (6.0 mL) at
-10 ◦C was added a solution of carbon tetrabromide (941 mg,
2.84 mmol) in CH2Cl2 (4.0 mL) dropwise. After being stirred at
-10 ◦C for 30 min, the reaction mixture was diluted with hexane.
The mixture was washed with H2O (3 times) and brine, dried over
Na2SO4 and concentrated under reduced pressure to give crude
allyl isocyanate 12, which was immediately used for subsequent
reaction.
MHz) d 1.10 (s, 9H), 1.36 (d, J = 7.0 Hz, 3H), 3.55 (s, 3H), 4.28
(quin, J = 7.0 Hz, 1H), 7.45–7.34 (m, 6H), 7.70–7.65 (m, 4H);
13C NMR (CDCl3, 100 MHz) d 19.2, 21.2, 26.8, 51.5, 68.9, 127.5,
127.6, 129.7, 133.1, 133.5, 135.7, 135.8, 174.1; HRMS (ESI): m/z
calcd for C20H26O3SiNa [M+ Na]+ 365.15489, found 365.1520.
(S,E)-Ethyl
4-(tert-butyldiphenylsilyloxy)-2-methylpent-2-
enoate (14). To a solution of silyl ether 8b (6.00 g, 17.5 mmol)
in CH2Cl2 (140 mL) cooled to -78 ◦C was added a solution
of diisobutylaluminium hydride (0.99 M in toluene, 21 mL,
21.0 mmol) dropwise. After being stirred at -78 ◦C for 1 h,
several drops of methanol were added to quench the reaction,
and aqueous potassium sodium (+)-tartrate tetrahydrate solution
was added. After stirring at room temperature for 30 min, the
separated aqueous layer was extracted with Et2O (3 times). The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure to
afford crude aldehyde (6.63 g), which was immediately used for
the subsequent reactions.
A mixture of tert-butyl alcohol (5.0 mL) and dry THF (3.0 mL)
at 0 ◦C was treated with n-butyllithium (1.58 M solution in
hexane, 1.30 mL, 2.03 mmol), and then allowed to warm to room
temperature. After stirring at room temperature for 30 min, the
◦
reaction mixture was recooled to -10 C and then a solution of
crude allyl isocyanate in THF (2.0 mL) was added. The reaction
◦
mixture was stirred at -10 C for 20 min, and then diluted with
H2O. The separated aqueous layer was extracted with Et2O (3
times). The combined organic layers were washed with H2O, brine,
and dried over anhydrous Na2SO4 and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (AcOEt–hexane 1 : 20) to afford Boc-carbamate
13 (206 mg, 81% from geraniol 9) as a colorless liquid.
To a solution of aldehyde in CH2Cl2 (140 mL) was added ethyl
2-(triphenylphosphoranylidene)propionate (19.0 g, 52.5 mmol).
After being stirred at room temperature for 18 h, the reaction
mixture was concentrated under reduced pressure. The crude
residue was purified by column chromatography (AcOEt–hexane
1 : 10) to give (E)-unsaturated ester 14 (6.35 g, 92%) as a colorless
liquid; [a]1D6 -53.6 (c 1.00, CHCl3); IR (NaCl) nmax 2693, 2931,
tert-Butyl 3,7-dimethylocta-1,6-dien-3-ylcarbamate (13) pre-
pared using method B. To a solution of allyl carbamate 10
(200 mg, 1.01 mmol), triphenylphosphine (665 mg, 2.53 mmol) and
triethylamine (0.45 mL, 3.24 mmol) in CH2Cl2 (6.0 mL) at -10 ◦C
was added a solution of carbon tetrabromide (941 mg, 2.84 mmol)
1
1714, 1111 cm-1; H NMR (CDCl3, 400 MHz) d 1.05 (s, 9H),
1.20 (d, J = 6.5 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H) 1.42 (s, 3H)
4.16 (quin, J = 7.0 Hz, 2H), 4.56 (dq, J = 8.5, 6.5 Hz, 1H) 6.72
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(d, J = 8.5 Hz, 1H) 7.45–7.31 (m, 6H), 7.68–7.60 (m, 4H); 13C
NMR (CDCl3, 100 MHz) d 12.2, 14.2, 19.1, 23.1, 26.9, 60.5, 66.7,
125.7, 127.3, 127.4, 127.6, 129.6, 129.6, 133.8, 134.1, 135.7, 135.8,
144.9, 168.0; HRMS (ESI): m/z calcd for C24H33O3Si (M+ H)+
397.21990, found 397.2198.
d 14.3, 19.1, 23.6, 26.9, 52.4, 66.3, 67.3, 122.4, 127.47, 127.52,
128.04, 128.16, 128.5, 129.41, 129.53, 129.56, 133.9, 134.2, 135.72,
135.79, 136.0, 137.4, 144.2, 154.4, 165.9; HRMS (ESI): m/z calcd
for C33H39NO5SiNa (M+ Na)+ 580.24952, found 580.2502.
(2S,6S,E)-Methyl 2-(benzyloxycarbonylamino)-6-(tert-butyl-
diphenylsilyloxy)-4-methylhept-4-enoate (17). Dry Schlenk
tube is charged with dienamide ester 16 (1.00 g, 1.79 mmol) and
methanol (20.0 mL). The mixture is degassed by three freeze–thaw
cycles and [(COD)Rh(S,S)-Et-DuPHOS]OTf (65 mg, 0.09 mmol,
5 mol%) was added. The resulting orange solution was further
degassed by three freeze–thaw cycles and then transferred by
syringe to a 50 mL glass autoclave equipped with a gas inlet tube
and pressure gauge. The gas inlet tube was attached to a hydrogen
source and then the autoclave was replaced by evacuation (to ca.
20 mmHg) and refilling with hydrogen three times. Hydrogen
was introduced into the reaction vessel until the pressure gauge
indicated 0.6 MPa. After stirring at room temperature for 21
h, the hydrogen was vented and the solvent was evaporated.
The crude material was purified by silica gel chromatography
(AcOEt–hexane 1 : 4) to afford g,d-unsaturated amino acid methyl
ether 17 (0.98 g, 98%) as a colorless liquid; [a]1D6 -22.6 (c 1.00,
(S,E)-4-(tert-Butyldiphenylsilyloxy)-2-methylpent-2-en-1-ol
(15). To a solution of unsaturated ester 14 (3.70 g, 9.34 mmol)
in CH2Cl2 (93 mL) cooled to -78 ◦C was added a solution
of diisobutylaluminium hydride (0.99 M in toluene, 22 mL,
21.5 mmol) dropwise. After being stirred at -78 ◦C for 1 h,
MeOH and aqueous potassium sodium (+)-tartrate solution were
added. After stirring at room temperature for 30 min, the separated
aqueous layer was extracted with Et2O (3 times). The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (AcOEt–hexane
1 : 4) to afford allyl alcohol 15 (2.91 g, 88%) as a colorless liquid;
[a]2D4 -6.6 (c 1.00, CHCl3); IR (NaCl) nmax; 3344, 2964, 2930, 2857
1
cm-1; H-NMR (CDCl3, 400 MHz): d 1.08 (s, 9H), 1.23 (d, J =
6.0 Hz, 3H), 1.25 (d, J = 1.0 Hz, 3H), 3.80 (s, 2H), 4.60 (dq,
J = 8.0, 6.0 Hz, 1H), 5.43 (dq, J = 8.0, 1.0 Hz, 1H), 7.33–7.73
(10H); 13C NMR (CDCl3, 100 MHz): d 13.5, 19.1, 24.2, 26.9,
66.4, 68.2, 127.3, 127.4, 129.36, 129.44, 130.5, 133.5, 134.4, 134.6,
135.7, 135.9; HRMS (ESI): m/z calcd for C22H30O2SiNa [M+Na]+
377.1913, found 377.1921.
1
CHCl3); IR (NaCl) nmax 3429, 3345, 2961,2930, 1724 cm-1; H
NMR (CDCl3, 400 MHz) d 1.00 (s, 9H), 1.11 (d, J = 6.5 Hz,
3H), 1.22 (brs, 3H), 2.20 (dd, J = 13.5, 8.0 Hz, 1H), 2.39 (dd,
J = 13.5, 6.5 Hz, 1H), 3.70 (s, 3H), 4.36 (q, J = 6.5 Hz, 1H),
4.44 (dq, t, J = 8.0, 6.5 Hz, 1H), 5.02–5.13 (3H), 5.31 (d, t, J =
8.0 Hz, 1H), 7.29–7.42 (11H), 7.58–7.68 (4H); 13C NMR (CDCl3,
100 MHz) d 15.4, 19.0, 24.2, 26.8, 42.1, 52.2, 66.4, 67.0, 127.39,
127.45, 128.12, 128.18, 128.44, 128.55, 129.5, 134.1, 134.4, 134.6,
135.70, 135.76136.1, 155.7, 172.8; HRMS (ESI): m/z calcd for
C33H41O5NSiNa [M+ Na]+ 582.26517, found 582.2655.
(S,2Z,4E)-Methyl 2-(benzyloxycarbonylamino)-6-(tert-butyl-
diphenylsilyloxy)-4-methylhepta-2,4-dienoate (16). To a solution
of allyl alcohol 15 (2.90 g, 8.19 mmol) dissolved in a mixture
of CH2Cl2 (82.0 mL) and aqueous solution (82.0 mL) of
NaHCO3 (0.5 M) and K2CO3 (0.05 M) were added TEMPO
(128 mg, 0.82 mmol) and tetrabutylammonium chloride (227 mg,
0.82 mmol). After vigorously stirring at room temperature for
10 min, N-chlorosuccinimide (1.90 g, 14.3 mmol) was added.
After being stirred at room temperature for 5 h, the organic
layer was separated, and the aqueous phase was extracted with
CH2Cl2 (2 times). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4 and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (AcOEt–hexane 1 : 20) to afford a
a,b-unsaturated aldehyde (2.71 g, 94%) as a colorless liquid.
To a solution of a,b-unsaturated aldehyde (2.39 g, 6.79 mmol)
in CH2Cl2 (23.0 mL) cooled to 0 ◦C were added methyl 2-
benzyloxycarbonylamino-2-(dimethoxyphosphinyl)acetate (7.40
g, 22.3 mmol) and 1,1,3,3-tetramethylguanidine (3.40 mL,
27.2 mmol). The reaction mixture was stirred at room temperature
for 4 days and quenched with saturated aqueous NH4Cl. The
aqueous layer was extracted with CH2Cl2 (3 times). The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4 and then concentrated under reduced pressure. The re-
sulting residue was purified by silica gel chromatography (AcOEt–
hexane 1 : 5) to afford Z-dienamide ester 16 (2.64 g, a colorless
liquid, 74%, calculated based on the consumed starting material),
recovered starting aldehyde (129 mg, 6%), and E-isomer (282 mg,
7%). [a]1D6 -85.9 (c 0.90, CHCl3); IR (NaCl) nmax 3317, 2931, 2857,
1715, 1633 cm-1; 1H NMR (CDCl3, 400 MHz) d 1.03 (s, 9H), 1.17
(d, J = 6.0 Hz, 3H), 1.40 (s, 3H), 3.76 (brs, 3H), 4.56 (dq, J = 8.0,
6.0 Hz, 1H), 5.12 (s, 2H), 5.85 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H),
7.29–7.43 (6H), 7.60–7.69 (4H); 13C NMR (CDCl3, 100 MHz)
(2S,6S,E)-Methyl
2-((benzyloxycarbonyl)(tert-butoxycarbo-
nyl)amino)-6-(tert-butyldiphenylsilyloxy)-4-methylhept-4-enoate
(19). To a solution of 17 (2.05 g, 3.67 mmol) and 4-
dimethylaminopyridine (0.45 g, 3.67 mmol) in dry THF
(37.0 mL) was added di-tert-butyl dicarbonate (3.80 mL,
16.4 mmol) at room temperature. After being stirred at 50 ◦C
for 28 h, the reaction mixture was diluted with water, and then
extracted with Et2O (3 times). The combined organic extracts were
washed with saturated aqueous NaHCO3 and brine, dried over
anhydrous Na2SO4 and then concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(AcOEt–hexane 1 : 10) to afford biscarbamate 19 (2.41 g, quant)
as a colorless liquid; [a]1D6 -44.9 (c 1.00, CHCl3); IR (NaCl) nmax
2965, 2931, 1748, 1702 cm-1; 1H NMR (CDCl3, 400 MHz) d 1.01
(s, 9H), 1.04 (d, J = 6.0 Hz, 3H), 1.31 (d, J = 1.0 Hz, 3H), 1.43 (s,
9H), 2.49 (dd, J = 14.5, 9.5 Hz, 1H), 2.75 (dd, J = 14.5, 5.5 Hz,
1H), 3.66 (s, 3H), 4.45 (dq, J = 8.0, 6.0 Hz, 1H), 5.10 (dd, t, J =
9.5, 5.5 Hz, 1H), 5.35 (brd, J = 8.0 Hz, 1H), 5.17–5.24 (2H),
7.29–7.42 (11H), 7.59–7.70 (4H); 13C NMR (CDCl3, 100 MHz)
d 16.3, 19.1, 24.2, 26.9, 27.9, 39.1, 52.2, 57.2, 66.7, 68.8, 83.5,
127.42, 127.43, 128.21, 128.29, 128.44, 129.32, 129.38, 129.8,
133.6, 134.2, 134.8, 135.2, 135.2, 135.75, 135.8, 151.2, 153.9,
170.9; HRMS (ESI): m/z calcd for C38H49O7NSiNa [M+Na]+
682.31760, found 682.3185.
(2S,6S,E)-Methyl 2-((benzyloxycarbonyl)(tert-butoxycarbonyl)-
amino)-6-hydroxy-4-methylhept-4-enoate (20). To a solution of
618 | Org. Biomol. Chem., 2012, 10, 614–622
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biscarbamate 19 (2.30 g, 3.49 mmol) and AcOH (1.20 mL,
20.9 mmol) in CH3CN (35.0 mL) was added dropwise tetrabuty-
lammonium fluoride (1.0 M solution in THF, 21.0 mL, 21.0 mmol)
at 0 ◦C. After stirring at 50 ◦C for 36 h, the reaction mixture was
cooled to room temperature and then diluted with water. The
aqueous layer was extracted with Et2O (3 times). The combined
organic extracts were washed with saturated aqueous NH4Cl,
saturated aqueous NaHCO3, and brine, dried over anhydrous
Na2SO4 and then concentrated under reduced pressure. The crude
material was purified by silica gel chromatography (AcOEt–
hexane 1 : 2) to afford allyl alcohol 20 (1.11 g, 75%) as a colorless
liquid; [a]1D6 -40.2 (c 1.00, CHCl3); IR (NaCl) nmax 3535, 2976,
The separated aqueous layer was extracted with ether, and the
combined organic extracts were washed with brine and dried
over Na2SO4. Concentration under reduced pressure followed by
purification by silica gel chromatography (AcOEt–hexane 1 : 4)
afforded Boc-carbamate 4 (1.58 g, 78%) as a colorless liquid; [a]D17
-14.1 (c 1.00, CHCl3); IR (NaCl) nmax 3378, 2977, 1796, 1725 cm-1;
1H NMR (CDCl3, 400 MHz) d 1.35 (s, 3H), 1.41 (s, 9H), 1.44 (s,
9H), 1.62 (d, J = 5.0 Hz, 3H), 2.18 (dd, J = 15.0, 6.5 Hz, 1H), 2.65
(dd, J = 15.0, 3.5 Hz, 1H), 3.65 (s, 3H), 5.20–5.28 (2H), 5.35–5.46
(2H), 7.33–7.44 (5H); 13C NMR (CDCl3, 100 MHz) d 17.8, 26.1,
27.9, 28.3, 41.0, 52.6, 54.9, 55.3, 68.8, 83.6, 123.2, 128.33, 128.37,
128.5, 135.2, 135.5, 151.1, 153.6, 171.9; HRMS (ESI): m/z calcd
for C27H40O8N2Na [M+ Na]+ 543.26823, found 543.2729.
1
1790, 1745, 1701 cm-1; H NMR (CDCl3, 400 MHz) d 1.16 (d,
J = 6.5 Hz, 3H), 1.44 (s, 9H), 1.64 (s, 3H), 2.62–2.73 (2H), 3.68
(s, 3H), 4.43 (m, 1H), 5.09 (dd, J = 10.0, 5.5 Hz, 1H), 5.03 (d, J =
8.5, 6.0 Hz, 1H), 5.23 (s, 2H), 7.33–7.42 (5H); 13C NMR (CDCl3,
100 MHz) d 16.1, 23.0, 27.8, 39.2, 52.3, 56.4, 64.3, 68.9, 128.46,
128.49, 128.52, 132.9, 133.6, 151.4, 153.8, 170; HRMS (ESI): m/z
calcd for C22H31O7NNa [M+Na]+ 444.19982, found 444.2011.
(2S,4R)-Methyl 2-((benzyloxycarbonyl)(tert-butoxycarbonyl)-
amino)-4-(tert-butoxycarbonylamino)-5-hydroxy-4-methylpenta-
noate (21). A stream of ozone in oxygen was bubbled through
a solution of Boc-carbamate 4 (481 mg, 0.92 mmol) and a trace
amount of Sudan IV in a mixture of CH2Cl2 and MeOH (6 : 1,
48 mL) at -78 ◦C for 5 min. Oxygen was bubbled through the
solution for 30 min and then dimethyl sulfide (0.68 ml, 9.2 mmol)
was added. After being stirring at -78 ◦C for 60 min and at
room temperature for 60 min, reaction mixture was cooled to
(2S,6S,E)-Methyl 2-((benzyloxycarbonyl)(tert-butoxycarbonyl)-
amino)-6-(carbamoyloxy)-4-methylhept-4-enoate (7). To a solu-
tion of allyl alcohol 20 (1.04 g, 2.47 mmol) in CH2Cl2 (15.0 mL)
cooled to 0 ◦C was added trichloroacetyl isocyanate (0.44 mL,
3.70 mmol). After stirring at 0 ◦C for 1 h, the solution was
concentrated under reduced pressure. The resulting residue was
dissolved in MeOH (15.0 mL) and then treated with triethylamine
(2.10 mL, 14.8 mmol). After stirring at room temperature for
3 h, the reaction mixture was quenched with saturated aqueous
NH4Cl. The aqueous layer was extracted with AcOEt (3 times).
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4 and then concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography
(AcOEt–hexane 1 : 2) to afford allyl carbamate 7 (1.12 g, 98%) as
a colorless liquid; [a]D17 -45.4 (c 1.00, CHCl3); IR (NaCl) nmax 3488,
3381, 2979, 1793, 1742, 1596 cm-1; 1H NMR (CDCl3, 400 MHz)
d 1.23 (d, J = 6.5 Hz, 3H), 1.46 (s, 9H), 1.69 (s, 3H), 2.65 (dd,
J = 14.0, 10.5 Hz, 1H), 2.74 (dd, J = 14.0, 5.0 Hz, 1H), 3.67 (s,
3H), 4.38 (brs, 2H), 5.11–5.16 (2H), 5.23 (s, 2H), 5.42 (dq, J = 8.5,
6.5 Hz, 1H), 7.32–7.43 (5H); 13C NMR (CDCl3, 100 MHz) d 16.4,
20.8, 27.8, 39.2, 52.3, 56.4, 68.2, 68.7, 83.5, 128.2, 128.3, 128.5,
129.0, 134.6, 135.2, 151.0, 153.5, 156.4, 170.7; HRMS (ESI): m/z
calcd for C23H32O8N2Na [M+Na]+ 487.20563, found 487.2068.
◦
-78 C and then treated with a solution of sodium borohydride
(699 mg, 18.5 mmol). The reaction mixture was warmed to
-10 ◦C and stirred at -10 ◦C for 30 min. Saturated aqueous
NaHCO3 was added at -78 ◦C, and the cooling bath was removed.
After stirring at room temperature for 60 min, the resulting
solution was extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4 and
then concentrated under reduced pressure. The resulting residue
was purified by silica gel chromatography (AcOEt–hexane 1 : 10
followed by 1 : 2) to afford alcohol 21 (430 mg, 89%) as a colorless
liquid; [a]2D7 -2.8 (c 1.02, CHCl3), [a]2D7 -8.5 (c 0.96, MeOH); IR
1
(NaCl) nmax 3393, 2978, 1793, 1747 cm-1; H NMR (CDCl3, 400
MHz) d 1.23 (s, 3H), 1.39 (s, 9H), 1.46 (s, 9H), 2.36 (dd, J = 15.5,
4.5 Hz, 1H), 3.53 (brd, J = 12.0 Hz, 1H), 3.60–3.65 (1H), 3.65
(s, 3H), 5.04–5.11 (2H), 5.21 (d, J = 12.0 Hz, 1H), 5.30 (d, J =
12.0 Hz, 1H), 7.30–7.44 (5H); 13C NMR (CDCl3, 100 MHz) d
22.3, 27.8, 28.3, 37.0, 52.7, 54.8, 55.8, 69.0, 69.3, 79.6, 84.0, 128.2,
128.4, 128.5, 135.0, 150.9, 153.7, 155.8, 172.1; HRMS (ESI): m/z
calcd for C25H39O5N2O9 [M+H]+ 511.26556, found 511.2647.
tert-Butyl
(3S,5R)-5-methyl-2-oxotetrahydro-2H-pyran-3,5-
(2S,4R,E)-Methyl
2-((benzyloxycarbonyl)(tert-butoxycarbo-
diyldicarbamate (22). A mixture of alcohol 21 (207 mg,
0.406 mmol) and palladium on carbon (10%, 23 mg) in MeOH
(4.0 mL) was stirred vigorously under a hydrogen atmosphere for
2 h. The reaction mixture was filtered through a pad of Celite
and the filtrate was concentrated under reduced pressure to
provide a mixture of deprotection product and lactone 22, which
was immediately dissolved in toluene (4.0 mL). The solution
was heated at 60 ◦C for 40 h and then concentrated to afford
the residue, which was purified by silica gel chromatography
(AcOEt–hexane 1 : 10 followed by 2 : 1) to◦ provide lactone 22
(106 mg, 76%) as a white solid; Mp 178–179 C (lit.1 Mp 177 ◦C);
[a]D18 = +120.3 (c 1.05, CHCl3) (lit.5 [a]D27 = +128, c 1.05, CHCl3);
IR (NaCl) nmax 3317, 3053, 2978, 1755, 1687, 1536 cm-1; 1H NMR
(CDCl3, 400 MHz) d 1.43 (s, 9H), 1.45 (s, 9H), 1.47 (s, 3H), 1.91
(dd, J = 14.0, 10.5 Hz, 1H), 2.65 (dd, J = 14.0, 8.5 Hz, 1H), 4.07
(d, J = 12.0 Hz, 1H), 4.42 (m, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.77
nyl)amino)-4-(tert-butoxycarbonylamino)-4-methylhept-5-enoate
(4). To a solution of allyl carbamate 7 (1.80 g, 3.88 mmol),
triphenylphosphine (2.54 g, 19.7 mmol) and triethylamine
(1.90 mL, 14.0 mmol) in CH2Cl2 (37 mL) at -10 ◦C was added a
solution of carbon tetrabromide (3.60 g, 10.9 mmol) in CH2Cl2
(2.0 mL) dropwise. After being stirred at -10 ◦C for 20 min,
the reaction mixture was diluted with hexane. The mixture was
washed with H2O and brine, dried over Na2SO4 and concentrated
under reduced pressure to give crude allyl isocyanate 5, which was
immediately used for the subsequent reaction.
Crude allyl isocyanate 5 was dissolved in a mixture of tert-butyl
alcohol (3.70 mL, 38.8 mmol) and CH2Cl2 (39.0 mL), and then
treated with trimethylchlorosilane (50 mL, 0.39 mmol) at room
temperature. After being stirred at room temperature for 7 days,
the reaction mixture was poured into aqueous saturated NaHCO3.
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(brs, 1H), 5.37 (brd, J = 5.5 Hz, 1H) (lit.5 CDCl3, 300 MHz, d 1.42
(s, 9H), 1.45 (s, 9H), 1.47 (s, 3H), 1.93 (dd, J = 13.8, 11.4 Hz, 1H),
2.64 (dd, J = 13.8, 8.2 Hz, 1H), 4.08 (d, J = 11.9 Hz, 1H), 4.39 (m,
1H), 4.45 (d, J = 11.9 Hz, 1H), 4.76 (s, 1H), 5.36 (d, J = 5.5 Hz,
1H)); 13C NMR (CDCl3, 100 MHz) d 23.4, 28.20, 28.27, 40.7,
47.3, 51.5, 72.7, 77.2, 79.9, 80.3, 154.4, 155.3, 172.0. (lit.5 CDCl3,
75 MHz, d 23.54, 28.30, 28.36, 40.91, 47.41, 51.56, 72.80, 80.07,
80.44, 154.44, 155.30, 171.99); Anal. Calcd for C28H28N2O6: C,
55.80; H, 8.19; N, 8.13. Found: C, 55.98; H, 8.47; N, 8.07.
5.2 Hz, 1H), 4.34 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H),
4.47 (dd, J = 10.0, 5.2 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 7.02 (d,
J = 1.6 Hz, 1H), 8.07 (s, 1H)); 13C NMR (CD3OD, 125 MHz) d
24.0, 31.0, 49.6, 53.8, 68.8, 98.2, 118.6, 123.2, 125.3, 152.1, 160.5,
171.3. (lit.:5 CD3OD, 75 MHz, d 24.05, 31.05, 53.82, 68.80, 98.18,
118.63, 123.24, 125.36, 152.19, 160.59; lit.:6e CD3OD, 75 MHz, d
24.1, 31.2, 53.8, 68.7, 98.1, 118.4, 123.1, 125.2, 151.9, 160.4, 172.8);
HRMS (ESI): m/z calcd for C12H15 BrN3O4 (M+ H)+ 346.0246 and
346.0267, found 344.0253 and 346.0245.
(4S,6R)-6-(Hydroxymethyl)-6-methyl-3,4,5,6-tetrahydropyri-
midine-4-carboxylic acid (3). To a solutio◦n of 22 (124 mg,
0.36 mmol) in CH2Cl2 (3.6 mL) cooled to 0 C was added TFA
(2.4 mL) and the cooling bath was removed. After stirring at
room temperature for 30 min, the mixture was concentrated under
reduced pressure to afford the residue, which was dissolved in
trimethyl orthoformate (3.0 mL). The solution was treated with
TFA (0.90 mL) at 0 ◦C, and was stirred at room temperature for
20 h. After concentration under reduced pressure, the resulting
residue was dissolved in 2 N HCl. After stirring at room
temperature for 2 h followed by concentration, the crude 3 was
purified by ion exchange chromatography (Dowex 50 W ¥ 8,
100–200 mesh, H+ form, eluted with H2O, then 1 N aqueous
NH3) to afford tetrahydropyrimidine 3 (55 mg, 89%), which was
ent-16. Starting from allyl alcohol ent-15 (1.60 g, 4.52 mmol),
CH2Cl2 (45.0 mL), aqueous solution (45.0 mL) of NaHCO3
(0.5 M) and K2CO3 (0.05 M), TEMPO (71 mg, 0.45 mmol),
tetrabutylammonium chloride (125 mg, 0.45 mmol) and N-
chlorosuccinimide (1.10 g, 7.9 mmol), a,b-unsaturated aldehyde
was obtained as a colorless liquid (1.45 g, 91%); [a]1D5 = +29.4 (c
1
1.00, CHCl3); IR (NaCl) nmax 3071, 2961, 2930, 1693 cm-1; H
NMR (CDCl3, 400 MHz) d 1.07 (s, 9H), 1.27 (d, J = 6.5 Hz,
3H), 1.33 (brs, 3H), 4.73 (dq, t, J = 8.0, 6.5 Hz, 1H), 6.40 (dd,
J = 7.5, 1.0 Hz, 1H), 7.30–7.47 (6H), 7.58–7.70 (4H), 9.28 (s, 1H);
13C NMR (CDCl3, 100 MHz) d 8.9, 19.1, 22.9, 26.8, 66.5, 127.58,
127.65, 129.79, 129.83, 133.5, 133.6, 135.7, 136.2, 156.5, 195.1.
Starting from a,b-unsaturated aldehyde (1.35 g, 3.83 mmol),
CH2Cl2 (38.0 mL), methyl 2-benzyloxycarbonylamino-2-
(dimethoxyphosphinyl)acetate (4.20 g, 12.6 mmol) and 1,1,3,3-
tetramethylguanidine (1.90 mL, 15.3 mmol), a mixture of
dienamide ester was obtained, which was purified by silica gel
chromatography (AcOEt–hexane 1 : 5) to afford Z-dienamide
ester ent-16 (1.22 g, a colorless liquid, 70%, calculated based
on the consumed starting material), a 1 : 1 mixture of Z- and
E-isomers (0.16 g, 8%), E-isomer (35 mg, 2%) and recovered
starting material (243 mg, 18%). The calculated selectivity (Z : E)
is approximately 91 : 9; [a]2D7 = +83.7 (c 1.00, CHCl3); IR (NaCl)
1
considered to be pure enough for the subsequent reaction by H
NMR analysis; [a]D23 = +45.7 (c 0.60, H2O) (lit.5 [a]2D2 = +57.3 (c
0.53, H2O)); 1H NMR (H2O, 500 MHz) d 1.25 (s, 3H), 1.83 (dd,
J = 14.0, 11.0 Hz, 1H), 2.08 (dd, J = 14.0, 5.0 Hz, 1H), 3.48 (d,
J = 11.5 Hz, 1H), 3.57 (d, J = 11.5 Hz, 1H), 4.05 (dd, J = 11.0,
5.0 Hz, 1H), 7.89 (s, 1H) (lit.,5 D2O, 500 MHz, d 1.28 (s, 3H), 1.86
(dd, J = 13.5, 10.7 Hz, 1H), 2.11 (dd, J = 13.5, 4.9 Hz, 1H), 3.51
(d, J = 11.8 Hz, 1H), 3.59 (d, J = 11.8 Hz, 1H), 4.08 (dd, J = 10.7,
4.9 Hz, 1H), 7.92 (s, 1H)); 13C NMR (D2O, 125 MHz) d 23.4, 31.0,
50.9, 54.6, 67.3, 150.8, 176.1 (lit.,5 D2O, 100 MHz, d 22.78, 30.46,
50.31, 54.09, 66.78, 150.28, 175.44); HRMS (ESI): m/z calcd for
C7H13 N2O3 (M+ H)+ 173.0926, found 173.0934.
1
nmax 3317, 2931, 2857, 1715, 1633 cm-1; H NMR (CDCl3, 400
MHz) d 1.03 (s, 9H), 1.18 (d, J = 6.0 Hz, 3H), 1.41 (s, 3H), 3.76
(brs, 3H), 4.56 (dq, J = 8.0, 6.0 Hz, 1H), 5.12 (s, 2H), 5.85 (d, J =
8.0 Hz, 1H), 5.95 (br, 1H), 6.84 (s, 1H), 7.29–7.43 (6H), 7.60–7.69
(4H); 13C NMR (CDCl3, 100 MHz) d 14.3, 19.1, 23.6, 26.8, 52.4,
66.3, 67.3, 122.4, 127.47, 127.53, 128.05, 128.18, 128.5, 129.40,
129.54, 129.57, 133.9, 134.2, 135.73, 135.80, 136.0, 137.4, 144.1,
154.4, 165.9; HRMS (ESI): m/z calcd for C33H39O5NSiNa [M+
Na]+ 582.26517, found 582.2657.
Manzacidin A (1). To a solution of 3 (55 mg, 0.32 mmol)
in DMF (3.0 mL) cooled to 0 ◦C was added sodium hydride
(64 mg, 60% dispersion in mineral oil, washed with hexane before
use, 1.6 mmol). After stirring at 0 ◦C for 1 h, bromopyrrole
(465 mg, 1.60 mmol) was added in one portion, and the cooling
bath was removed. After stirring at room temperature for 3 h, the
reaction mixture was quenched with 2 N HCl and washed with
AcOEt to remove excess bromopyrrole. The aqueous layer was
concentrated under reduced pressure to afford the residue, which
was subjected to reversed-phase chromatography (flash column of
Cosmosil 75C18-OPN eluted with water–acetonitrile 1 : 0 to 7 : 3,
and HPLC with Develosil ODS-UG-5, Nomura Chemical eluted
with acetonitrile–water–TFA = 22 : 78 : 0.1) to furnish manzacidin
A (1) (50 mg, 46%); [a]D24 -23.1 (c 0.50, CH3OH) (lit.4 [a]2D7 -28, c
0.67, CH3OH; lit.5 [a]D27 -22.4, c 0.52, CH3OH; lit.6a [a]2D7 -26.5, c
0.65, CH3OH; lit.6a [a]D29 -23.0, c 0.50, CH3OH; lit.6e [a]D25 -26.3,
c 0.30, CH3OH; lit.6j [a]D29 -21.8, c 1.09, CH3OH); IR (KBr) nmax
3198, 2984, 1676, 1319, 1202 cm-1; 1H NMR (CD3OD, 500 MHz)
d 1.46 (s, 3H), 2.22 (dd, J = 14.0, 10.0 Hz, 1H), 2.38 (dd, J =
14.0, 5.0 Hz, 1H), 4.23 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz,
1H), 4.48 (dd, J = 10.0, 5.0 Hz, 1H), 6.92 (d, J = 1.4 Hz, 1H),
7.03 (d, J = 1.4 Hz, 1H), 8.08 (s, 1H). (lit.:5 CD3OD, 75 MHz, d
1.47 (s, 3H), 2.20 (dd, J = 13.7, 10.0 Hz, 1H), 2.38 (dd, J = 13.7,
(2S,6R,E)-Methyl 2-(benzyloxycarbonylamino)-6-(tert-butyl-
diphenylsilyloxy)-4-methylhept-4-enoate (18). Starting from
dienamide ester ent-16 (1.01 g, 1.81 mmol), methanol (18.0 mL)
and [(COD)Rh(S,S)-Et-DuPHOS]OTf (65 mg, 0.091 mmol, 5
mol%), g,d-unsaturated amino acid methyl ether 18 (0.81 g, 80%)
was obtained as a colorless liquid; [a]2D7 = +27.2 (c 1.00, CHCl3);
IR (NaCl) nmax 3423, 3344, 2961, 2930, 1725 cm-1; 1H NMR
(CDCl3, 400 MHz) d 1.02 (s, 9H), 1.10 (d, J = 6.5 Hz, 3H), 1.23
(brs, 3H), 2.17 (dd, J = 13.5, 8.5 Hz, 1H), 2.38 (dd, J = 13.5,
4.5 Hz, 1H), 3.71 (s, 3H), 4.39 (td, J = 8.5, 4.5 Hz, 1H), 4.46 (dq,
J = 8.0, 6.5 Hz, 1H), 5.00–5.11 (3H), 5.29 (brd, J = 8.5 Hz, 1H),
7.29–7.44 (11H), 7.60–7.69 (4H); 13C NMR (CDCl3, 100 MHz) d
15.7, 19.1, 24.2, 26.9, 42.5, 52.1, 52.3, 66.5, 66.9, 127.37, 127.46,
128.03, 128.10, 128.4, 128.7, 129.4, 129.5, 134.2, 134.4, 134.7,
135.73, 135.76, 136.2, 155.6, 172.6; HRMS (ESI): m/z calcd for
C33H41O5NSiNa [M+ Na]+ 582.26517, found 582.2657.
620 | Org. Biomol. Chem., 2012, 10, 614–622
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(2S,6R,E)-Methyl
2-((benzyloxycarbonyl)(tert-butoxycarbo-
5.0 Hz, 3H), 2.39 (br, 1H), 2.53 (brd, J = 14.5 Hz, 1H), 3.64 (s,
3H), 5.01 (dd, J = 7.0, 3.0 Hz, 1H), 5.18–5.32 (2H), 5.39–5.46
(2H), 7.30–7.44 (5H); 13C NMR (CDCl3, 100 MHz) d 17.8, 25.6,
27.9, 28.3, 39.9, 52.5, 55.2, 55.7, 68.8, 78.9, 83.6, 123.5, 128.28,
128.33, 128.5, 151.1, 153.6, 154.4, 171.6; HRMS (ESI): m/z calcd
for C27H41N2O8 [M+H]+ 521.2863, found 521.2857.
nyl)amino)-6-(tert-butyldiphenylsilyloxy)-4-methylhept-4-enoate
(23a). Carbamate 18 (708 mg, 1.27 mmol) was transformed
into biscarbamate 23a (0.66 g, 79%) by employing 4-
dimethylaminopyridine (155 mg, 1.27 mmol), di-tert-butyl
dicarbonate (1.30 mL, 5.70 mmol) and THF (13.0 mL); [a]D19
-11.9 (c 1.25, CHCl3); IR (NaCl) nmax 2965, 2932, 1747, 1701
(2S,4S)-Methyl 2-((benzyloxycarbonyl)(tert-butoxycarbonyl)-
amino)-4-(tert-butoxycarbonylamino)-5-hydroxy-4-methylpenta-
noate. Boc-carbamate 24 (90 mg, 0.17 mmol) was transformed
into alcohol (66 mg, 75%) employing CH2Cl2 (7.7 mL), MeOH
(1.3 mL), ozone, dimethyl sulfide (0.13 mL, 1.7 mmol) and a
solution of sodium borohydride (131 mg, 3.46 mmol) in MeOH
(1.0 mL); [a]1D8 -15.5 (c 1.05, CHCl3); IR (NaCl) nmax 3500, 3416,
1
cm-1; H NMR (CDCl3, 400 MHz) d 1.02 (s, 9H), 1.03 (d, J =
6.5 Hz, 3H), 1.14 (brs, 3H), 1.42 (s, 9H), 2.50 (dd, J = 13.5, 4.5 Hz,
1H), 2.59 (dd, J = 13.5, 4.5 Hz, 1H), 3.66 (s, 3H), 4.39 (dq, J = 8.5,
6.5 Hz, 1H), 5.01 (dd, t, J = 11.0, 4.5 Hz, 1H), 5.14–5.09 (3H),
7.28–7.44 (11H), 7.60–7.68 (4H); 13C NMR (CDCl3, 100 MHz) d
15.5, 19.1, 24.2, 26.9, 27.8, 39.3, 52.2, 56.2, 66.5, 68.7, 83.4, 127.3,
127.4, 128.34, 128.37, 128.44, 129.33, 129.40, 129.46, 134.3, 134.4,
134.5, 135.1, 135.7, 135.8, 151.2, 153.7, 170.9; HRMS (ESI): m/z
calcd for C38H49O7NSiNa [M+ Na]+ 682.31760, found 682.3184.
1
2978, 1791, 1747 cm-1; H NMR (CDCl3, 400 MHz) d 1.24 (s,
3H), 1.42 (s, 9H), 1.45 (s, 9H), 1.97 (dd, J = 15.5, 5.0 Hz, 1H),
2.74 (dd, J = 15.5, 5.0 Hz, 1H), 3.50–3.60 (2H), 3.66 (s, 3H), 5.10
(br, 1H), 5.12 (t, J = 5.0 Hz, 1H), 5.22–5.30 (2H), 7.32–7.43 (5H);
13C NMR (CDCl3, 100 MHz) d 22.3, 27.8, 28.3, 38.2, 52.7, 54.8,
55.9, 69.0, 79.6, 84.0, 128.3, 128.41, 128.48, 135.1, 151.2, 153.7,
155.7, 172.3; HRMS (ESI): m/z calcd for C25H39ON2O9 [M+H]+
511.2656, found 511.2647.
(2S,6R,E)-Methyl
nyl)amino)-6-hydroxy-4-methylhept-4-enoate
2-((benzyloxycarbonyl)(tert-butoxycarbo-
(23b). Starting
from biscarbamate 23a (203 mg, 0.31 mmol), AcOH (0.11 mL,
1.85 mmol), CH3CN (3.1 mL) and tetrabutylammonium fluoride
(1.0 M solution in THF, 1.80 mL, 1.80 mmol), allyl alcohol 23b
was obtained as a colorless liquid (112 mg, 86%); [a]1D8 -23.1 (c
1.00, CHCl3); IR (NaCl) nmax 3524, 3418, 2976, 1747, 1698 cm-1;
1H NMR (CDCl3, 400 MHz) d 1.11 (d, J = 6.5 Hz, 3H), 1.44
(s, 9H), 1.65 (d, J = 1.0 Hz, 3H), 2.64–2.73 (2H), 3.68 (s, 3H),
4.46 (m, 1H), 5.09–5.16 (2H), 5.21 (s, 2H), 7.31–7.41 (5H); 13C
NMR (CDCl3, 100 MHz) d 16.1, 23.3, 27.8, 39.3, 52.3, 56.4,
64.5, 68.7, 83.6, 128.39, 128.41, 128.5, 132.6, 133.5, 135.0, 151.2,
153.7, 170.7; HRMS (ESI): m/z calcd for C22H31O7NNa [M+
Na]+ 444.19982, found 444.2016.
tert-Butyl
(3S,5S)-5-methyl-2-oxotetrahydro-2H-pyran-3,5-
diyldicarbamate (25). Starting from alcohol 24 (56 mg,
0.11 mmol), palladium on carbon (10%, 6 mg), MeOH (2.0 mL)
and toluene (2.0 mL), lactone 25 was produced as a white solid
(32 mg, 85%); Mp 171–172 ◦C; [a]D24 = +19.1 (c 1.10, CHCl3) (lit.5
[a]2D7 = +21.5, c 1.10, CHCl3); IR (NaCl) nmax 3332, 2978, 2932,
1
1713, 1692, 1170 cm-1; H NMR (CDCl3, 500 MHz) d 1.39 (s,
3H), 1.45 (s, 9H), 1.44 (s, 9H), 1.67 (t, J = 12.5 Hz, 1H), 2.72 (br,
1H), 4.24 (br, 1H), 4.44–4.62 (2H), 4.74 (br, 1H), 5.29 (br, 1H)
(lit.5 CDCl3, 300 MHz, d 1.38 (s, 3H), 1.43 (s, 9H), 1.44 (s, 9H),
1.66 (t, J = 12.9 Hz, 1H), 2.71 (m, 1H), 4.23 (m, 1H), 4.57 (m, 2H),
4.78 (s, 1H), 5.30 (brs, 1H)); 13C NMR (CDCl3, 125 MHz) d 25.8,
28.3, 39.7, 47.8, 50.7, 73.7, 80.3, 154.5, 155.1, 173.0 (lit.5 CDCl3,
100 MHz, d 28.29, 29.66, 39.66, 47.78, 50.67, 73.65, 80.30, 154.52,
155.16, 172.05); Anal. Calcd for C28H28N2O6: C, 55.80; H, 8.19;
N, 8.13. Found: C, 55.91; H, 8.43; N, 7.96; HRMS (ESI): m/z
calcd for C16H29N2O6 [M+H]+ 345.20256, found 345.2022.
(2S,6R,E)-Methyl
2-((benzyloxycarbonyl)(tert-butoxycarbo-
nyl)amino)-6-(carbamoyloxy)-4-methylhept-4-enoate (23c). Allyl
alcohol 23b (91 mg, 0.22 mmol) was transformed into allyl
carbamate 23c (94 mg, 94%) by employing CH2Cl2 (1.30 mL),
trichloroacetyl isocyanate (40 mL, 0.32 mmol), MeOH (1.30 mL)
and triethylamine (0.18 mL, 1.30 mmol); [a]2D4 -27.2 (c 1.08,
CHCl3); IR (NaCl) nmax 3481, 3380, 2979, 1792, 1730, 1597 cm-1;
1H NMR (CDCl3, 400 MHz) d 1.13 (d, J = 6.5 Hz, 3H), 1.44 (s,
9H), 1.69 (d, J = 1.0 Hz, 3H), 2.68–2.74 (2H), 3.68 (s, 3H), 4.53
(br, 2H), 5.08 (dd, J = 8.5, 1.0 Hz, 1H), 5.12 (dd, J = 8.5, 7.0 Hz,
1H), 5.22 (s, 2H), 5.38 (dq, J = 8.5, 6.5 Hz, 1H), 7.30–7.42 (5H);
13C NMR (CDCl3, 100 MHz) d 16.2, 20.7, 27.8, 39.4, 52.3, 56.2,
68.4, 68.8, 83.5, 128.36, 128.43, 128.46, 129.3, 134.5, 135.0, 151.1,
153.6, 156.4, 170.6; HRMS (ESI): m/z calcd for C23H32N2O8Na
[M+Na]+ 487.20563, found 487.2052.
Acknowledgements
We thank Professor Ohfune (Osaka City University) for informing
us about the detailed experimental procedures at the final stage of
his manzacidin synthesis. Professors Masato Oikawa (Yokohama
City University) and Tetsuo Shinada (Osaka City University) are
greatly acknowledged for advice on high-pressure hydrogenation
apparatus. We are grateful for the financial support provided by a
Grant-in-Aid for Scientific Research on Priority Areas (18032055)
from MEXT and Nagase Science and Technology Foundation.
(2S,4S,E)-Methyl
2-((benzyloxycarbonyl)(tert-butoxycarbo-
nyl)amino)-4-(tert-butoxycarbonylamino)-4-methylhept-5-enoate
(24). Starting from allyl carbamate 23c (94 mg, 0.22 mmol),
triphenylphosphine (146 mg, 0.56 mmol), triethylamine (0.11 mL,
0.80 mmol), CH2Cl2 (2.20 mL), carbon tetrabromide (207 mg,
0.62 mmol) in CH2Cl2 (2.0 mL), crude allyl isocyanate was
obtained. Without purification, crude allyl isocyanate was
transformed into Boc-carbamate 24 (90 mg, 77%) using CH2Cl2
(2.20 mL), trimethylchlorosilane (3 mL, 0.02 mmol) and tert-butyl
alcohol (0.43 mL, 4.46 mmol); [a]2D6 -16.0 (c 1.05, CHCl3); IR
Notes and references
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2 (a) S. H. Kang, S. Y. Kang, H. Lee and A. Buglass, A. J., Chem. Rev.,
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(NaCl) nmax 3433, 3383, 2977, 1798, 1746, 1742 cm-1; H NMR
(CDCl3, 400 MHz) d 1.39 (s, 12H), 1.46 (s, 9H), 1.64 (d, J =
1
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18 If epimerization of the a-stereogenic center in the a-amino acid ester 4
(Scheme 5) occurred, diastereomer ii should be formed. On the other
1
hand, ii is an enantiomer of 24 (Scheme 7). H NMR analysis of the
product 4 showed that no signals corresponding to those of 24 were
presented, which confirmed that the a-stereocenter in the a-amino acid
ester 7 did not epimerize in the conversion of 7 to 4.
10 W. J. Bailey and J. R. Griffith, J. Org. Chem., 1978, 43, 2690.
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622 | Org. Biomol. Chem., 2012, 10, 614–622
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